Effective Melanoma Immunotherapy in Mice by the Skin-Depigmenting Agent Monobenzone and the Adjuvants Imiquimod and CpG

Boorn, Jasper G. van den; Konijnenberg, Debby; Tjin, Esther P.M.; Picavet, Daisy I.; Meeuwenoord, Nico J.; Filippov, Dmitri V.; Veen, J.P.W. van der; Bos, Jan D.; Melief, Cornelis J.M.; Luiten, Rosalie M.

doi:10.1371/journal.pone.0010626

Cited by 28 publications

(49 citation statements)

References 46 publications

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“…While our studies investigate CD8 T cell-mediated vitiligo induced by melanoma, in the future it would be interesting to determine if these findings extend to other models of melanocyte destruction (e.g. vitiligo initiated by melanocytoxic chemicals (26, 27), monoclonal antibodies (28), or pathogenic CD4 T cells(29)).…”

Section: Discussionmentioning

confidence: 92%

Autoimmune Vitiligo Does Not Require the Ongoing Priming of Naive CD8 T Cells for Disease Progression or Associated Protection against Melanoma

Byrne

Zhang

Steinberg

et al. 2014

The Journal of Immunology

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Vitiligo is a CD8 T cell-mediated autoimmune disease that has been shown to promote the longevity of memory T cell responses to melanoma. However mechanisms whereby melanocyte/melanoma antigen-specific T cell responses are perpetuated in the context of vitiligo are not well understood. The present studies investigate the possible phenomenon of naïve T cell priming in hosts with melanoma-initiated, self-perpetuating, autoimmune vitiligo. Using naïve pmel (gp10025-33-specific) transgenic CD8 T cells, we demonstrate that autoimmune melanocyte destruction induces naive T cell proliferation in skin-draining lymph nodes, in an antigen-dependent fashion. These pmel T cells upregulate expression of CD44, P-selectin ligand, and granzyme B. However, they do not downregulate CD62L, nor do they acquire the ability to produce IFN-γ, indicating a lack of functional priming. Accordingly, adult thymectomized mice exhibit no reduction in the severity or kinetics of depigmentation or long-lived protection against melanoma, indicating that the continual priming of naïve T cells is not required for vitiligo or its associated anti-tumor immunity. Despite this, depletion of CD4 T cells during the course of vitiligo rescues the priming of naïve pmel T cells that are capable of producing IFN-γ and persisting as memory, suggesting an ongoing and dominant mechanism of suppression by regulatory T cells. This work reveals the complex regulation of self-reactive CD8 T cells in vitiligo, and demonstrates the overall poorly immunogenic nature of this autoimmune disease setting.

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Section: Discussionmentioning

confidence: 92%

Autoimmune Vitiligo Does Not Require the Ongoing Priming of Naive CD8 T Cells for Disease Progression or Associated Protection against Melanoma

Byrne

Zhang

Steinberg

et al. 2014

The Journal of Immunology

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“…We demonstrated that monobenzoneinduced depigmentation on non-exposed locations and drugexposed sites, indicating a systemic immune reaction to autologous melanocytes. The effect of monobenzone on promoting melanocyte antigen-specific immune response has been suggested by the fact that monobenzone and adjuvants imiquimod and CpG promptly suppressed melanoma growth in mice (13). Monobenzone can form quinone-haptens to the tyrosinase which in turn increase melanocyte cell immunogenicity (14).…”

Section: Discussionmentioning

confidence: 99%

A mouse model of vitiligo induced by monobenzone

Zhu

Wang

2013

Experimental Dermatology

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The paucity of vitiligo animal models limits the understanding of vitiligo pathogenesis and the development of therapies for the skin disorder. In this study, we developed a new mouse model of vitiligo by topically applying the skindepigmenting agent monobenzone on mice. We demonstrated that monobenzone-induced skin depigmentation on the nonexposed sites and that the severity of lesions depended on drug dosage. The result of the histological examination of the depigmented skin indicated loss of epidermal melanocytes and perilesional accumulation of CD8 + T cells. Furthermore, the monobenzone-induced depigmentation of the Rag1 gene knockout did not appear on the non-exposed sites, supporting the involvement of infiltrating CD8 + T cells in melanocyte destruction. Resemblance in histological characteristics and pathogenesis between monobenzone-induced depigmentation and active human vitiligo suggests good potential of our mouse model for use in vitiligo research.

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“…The idea that melanocyte death drives CD8 + T cell responses to melanoma is supported by published reports that the targeted killing of melanocytes with cytotoxic vectors (36,37), or the melanocytotoxic chemical monobenzone (38), primes robust and long-lived T cell immunity to B16 melanoma. The present studies demonstrate that such stimuli are provided naturally to memory T cells in hosts with vitiligo.…”

Section: Figurementioning

confidence: 98%

Autoimmune melanocyte destruction is required for robust CD8+ memory T cell responses to mouse melanoma

Byrne¹,

Côté²,

Zhang³

et al. 2011

J. Clin. Invest.

105

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A link between autoimmunity and improved antitumor immunity has long been recognized, although the exact mechanistic relationship between these two phenomena remains unclear. In the present study we have found that vitiligo, the autoimmune destruction of melanocytes, generates self antigen required for mounting persistent and protective memory CD8 + T cell responses to melanoma. Vitiligo developed in approximately 60% of mice that were depleted of regulatory CD4 + T cells and then subjected to surgical excision of large established B16 melanomas. Mice with vitiligo generated 10-fold larger populations of CD8 + memory T cells specific for shared melanoma/melanocyte antigens. CD8 + T cells in mice with vitiligo acquired phenotypic and functional characteristics of effector memory, suggesting that they were supported by ongoing antigen stimulation. Such responses were not generated in melanocyte-deficient mice, indicating a requirement for melanocyte destruction in maintaining CD8 + T cell immunity to melanoma. Vitiligo-associated memory CD8 + T cells provided durable tumor protection, were capable of mounting a rapid recall response to melanoma, and did not demonstrate phenotypic or functional signs of exhaustion even after many months of exposure to antigen. This work establishes melanocyte destruction as a key determinant of lasting melanoma-reactive immune responses, thus illustrating that immune-mediated destruction of normal tissues can perpetuate adaptive immune responses to cancer.

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Effective Melanoma Immunotherapy in Mice by the Skin-Depigmenting Agent Monobenzone and the Adjuvants Imiquimod and CpG

Cited by 28 publications

References 46 publications

Autoimmune Vitiligo Does Not Require the Ongoing Priming of Naive CD8 T Cells for Disease Progression or Associated Protection against Melanoma

Autoimmune Vitiligo Does Not Require the Ongoing Priming of Naive CD8 T Cells for Disease Progression or Associated Protection against Melanoma

A mouse model of vitiligo induced by monobenzone

Autoimmune melanocyte destruction is required for robust CD8+ memory T cell responses to mouse melanoma

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